: In the U.S. 5% of women over age 60, 12% of those over age 75%, and as many as 28% of women past 85 years of age may be demented. The proposed study capitalized on the availability of a large and powerful epidemiologic dataset to advance the knowledge of potential risk factors for cognitive impairment. We propose to examine prospectively how estrogen use, dietary antioxidants especially vitamin E supplements, and genetic factors influence the development of cognitive decline in a group of women who are free of major illness at baseline. The interactions between environmental exposures and genetic factors will also be explored. The investigation investigation will be conducted within the Nurse's Health Study, a prospective cohort study begun in 1976 with 121,700 women. Extensive data have been accumulated from the women regarding lifestyle exposures and disease outcomes via biennial mail questionnaires. Information on hormone use includes currency of use, duration, dose, and type. For vitamin E, the currency of use and dosage have been reported since 1980. In 1989 blood samples were collected from 33,000 of the women; to accommodate the proposed analyses, all study subjects will be chosen from those who provided blood samples. We will conduct repeated tests of cognitive function by telephone to a group of 4,500 women aged 73-78 using a well-established and validated instrument. Baseline data from this testing will serve as the initiation of a prospective study of predictors of cognitive decline. Second interviews will be given to the same woman after a 2 year interval and in a sample a third test will be given at 4 years. A pilot study of the cognitive function test in approximately 500 Nurse's Health Study participants was highly successful; the participation rate was 92% and 10% of the subjects had scores which indicated cognitive dysfunction. Dementia is an increasingly important cause of death and disability, yet very little is known about ways to preserve cognitive function. Most prior investigations have been cross-sectional and smaller than the proposed study. In addition, while genetic aspects of dementia are increasingly being appreciated, virtually no studies have explored interactions between environmental and genetic factors. The Nurse's Health Study provides a highly cost efficient setting to investigate several lifestyle modification as well as genetic influences, which may be instrumental in preventing or delaying decline in cognitive function.